Infertility is a common health condition that affects 10-15% of American couples. It is estimated that genetic factors contribute to nearly 50% of idiopathic (unknown cause) infertility. Yet, a majority of infertile males do not receive a genetc diagnosis. About 7% of infertile men are diagnosed with azoospermia (AZ), a heterogeneous pathology with complete loss of spermatozoa in the seminal fluid. Current genetic testing of idiopathic AZ is limited to karyotyping and Y-chromosome microdeletion, which detect chromosome abnormalities in only 15% of AZ patients. Widespread assisted reproductive technologies (ART), while helping many couples, could introduce genetically inherited infertility to ART-assisted offspring. Thus, it is critical to understand the genetic etiologies of male infertility for both the diagnosis and treatment of the infertile male. A wealth of evidence from animal knockout models suggests that many X-linked and autosomal gene mutations could contribute to spermatogenesis arrest and azoospermia. We propose to apply two compelling genomic approaches: a custom-designed X-chromosome array CGH analysis and Whole Exome next generation sequencing. Using these comprehensive approaches we will examine the contribution of genomic abnormalities and mutations in all coding genes, including all 1659 X-linked and 944 known autosomal AZ candidate genes to idiopathic azoospermia. We hypothesize that our efforts will lead to the discovery of novel genetic defects responsible for significant proportion of AZ, spurring the a clinical diagnostic testing of azoospermia and likely transforming clinical care of male infertility. Moreover, we anticipate discovering novel molecular pathways relevant to human azoospermia that will further stimulate basic and clinical investigations of male infertility.